Optimizing Longitudinal Tobacco Cessation Treatment in Lung Cancer Screening

Key Points Question Does adding a referral to pharmacy for prescription medication therapy management (MTM) to the evidence-based tobacco longitudinal care (TLC) program improve smoking abstinence rates compared with TLC without MTM among patients who are eligible for lung cancer screening (LCS), who smoke, and who do not respond to early tobacco treatment? Findings In this randomized clinical trial of 636 patients who were eligible for LCS and smoked daily, adding a referral to MTM with TLC for participants who did not respond to initial TLC treatment did not improve long-term smoking abstinence (17.8% vs 16.4%). Meaning These findings suggest that TLC was most effective when implemented without modification.


Introduction
The landmark National Lung Screening Trial demonstrated that annual low-dose computerized tomography (LDCT) for lung cancer screening (LCS) reduces lung cancer death by 20%. [1][2][3] Since 2013, annual LDCT has been recommended for adults aged 55 to 80 years with a 30 pack-year or more smoking history and who currently smoke or have quit within the past 15 years. [4][5][6][7] To address lung cancer disparities by sex and race or ethnicity 8,9 the eligible population was expanded in 2021 to adults aged 50 to 80 years and a 20 pack-year or more smoking history (14.8 million estimated). 10 About 48% of patients eligible for LCS currently smoke cigarettes. 11 Annual LCS creates a clinical obligation to develop and implement efficient and effective programs to address smoking in the LCS setting. Furthermore, patients who quit smoking and complete annual LDCT screening experience the greatest mortality reduction. 12 Clinical trials have established the efficacy of behavioral treatment, medication treatment, and combination behavioral and medication treatment for long-term smoking cessation. 13 However, the optimal smoking cessation program components for the LCS setting are unclear. 14,15 One approach to improving long-term abstinence rates is the use of adaptive interventions. Adaptive interventions describe how to sequence treatment options (such as type, frequency, delivery mode) using information about individuals, including response to previous interventions. For example, for individuals showing early signs of difficulty with quitting, adaptive interventions might dictate which additional treatment to deliver and its timing. Adaptive interventions can also suggest treatment options for individuals who experience early success with quitting. 16 Interventions that adapt to the changing needs and experiences of the individual are key to the management of chronic diseases like smoking. 17 Incorporating chronic care model 18,19 principles, the Tobacco Longitudinal Care (TLC) program is tobacco treatment comprised of intensive telephone coaching and combination nicotine replacement therapy (NRT). 17 A unique feature of TLC is that the program encourages participants who relapse to set a new quit date and if they are unwilling to do so, to try to reduce their smoking in anticipation of setting a new quit date.
TLC delivered for 1 year was previously demonstrated to be efficacious in a confirmatory, randomized clinical trial. 17 The current study reports the main results of the Program for Lung Cancer Screening and Tobacco Cessation (PLUTO) trial. 20  PLUTO used a 2-stage, sequential, multiple assignment, randomized trial (SMART) design. [22][23][24] SMART trials are not confirmatory randomized trials; rather, they are designed to provide evidence for how best to construct an adaptive intervention. 25 The primary aim was to assess the effect of adding referral to prescription medication therapy management (MTM) to TLC among participants who did not respond early to smoking cessation treatment (hereafter referred to as early treatment nonresponders, defined as any smoking, even a puff, in the last 7 days). 26 We hypothesized that among early treatment nonresponders, long-term abstinence rates (primary outcome) would be higher in participants randomized to TLC with MTM compared with TLC alone without MTM. Our secondary aim assessed the effect of decreasing the intensity of the TLC program from at least monthly contact to at least quarterly contact among participants who did respond to early treatment (hereafter referred to as early treatment responders, defined as no smoking, even a puff, in the last 7 days). We hypothesized that more intensive follow-up would improve long-term abstinence rates.

Study Design Overview
The PLUTO trial was approved by the institutional review boards at the University of Minnesota, the Minneapolis Veterans Affairs Health Care System, and the Allina Health System. Written informed consent was obtained. The study protocol and methods have been previously described (Supplement 1). 20 Participants received 1 of 3 TLC-based interventions based on defined decision rules (Figure 1) for 1 year. Each participant was randomized twice. In stage 1, all participants initiated TLC and were randomized to assess early response to TLC treatment at either 4 weeks vs 8 weeks (randomization 1, the results of which are not included in this article). In stage 2, participants were randomized to different interventions. Early treatment nonresponders were randomized to continue TLC with a minimum of monthly contact or TLC with MTM (randomization 2A). MTM provided access to prescription medications delivered by a pharmacist with prescribing privileges. Early treatment responders were randomized to continue TLC with a minimum of monthly contact or TLC with less

Study Participants
Inclusion criteria were having LDCT for LCS scheduled or ordered or being LCS eligible, currently smoking daily, being 55 to 80 years old, and being willing to choose a quit date within the next 12 weeks. Exclusion criteria were having an unstable psychiatric disease or cognitive impairment, currently participating in smoking cessation treatment, not having a phone, or not speaking English.  Six scheduled counseling calls were provided during the first 4 weeks and a seventh call at week 8. After this initial sequence of calls, participants were contacted at least monthly by their coach, but the frequency of calls may have been higher around quit dates after relapse. The focus of counseling was cessation. Combination NRT was recommended 27 and mailed free of charge by the coach.

TLC With MTM
In TLC with MTM, TLC was expanded to include referral and consultation with a pharmacist to prescribe bupropion, varenicline, nicotine spray, nicotine inhaler, or combination medications (eg, bupropion with NRT). Because this was a pragmatic trial, participants could decline referral. If referred, participants were not obliged to use medications, but pharmacists promoted their use.

Quarterly TLC
Early treatment responders were assigned to receive continued TLC or Quarterly TLC and counselors called participants every 3 months for 1 year. They provided the same coaching options as TLC, but on a less intensive schedule. Participants could initiate additional calls.

Research Data Sources and Data Collection
Data sources included telephone surveys, the EMR, and counselor records. PLUTO provided financial incentives for completing research surveys ($20 to $25) but not for treatment participation.
Research assistants involved in data collection were blinded to intervention assignments.

Outcome Measures
The primary outcome was self-reported, 6-month prolonged abstinence at 18 months 26 ; smoking at least once on 7 consecutive days or at least once on 2 consecutive weekends in the 6-month period defined nonabstinence. Initial biochemical verification of smoking abstinence with salivary cotinine was disrupted by the COVID-19 pandemic in March 2020. In May 2020, we attempted to use CO (carbon monoxide) smokelyzers to verify smoking abstinence 28 ; however, product availability was limited and the data safety and management board approved a protocol change to self-reported 6-month prolonged abstinence as the primary outcome. Secondary outcomes included 7-day point prevalence abstinence at 12 months and 18 months; any smoking in the past 7 days, even a puff, defined nonabstinence.

Sample Size and Power Analysis
The sample size was chosen to ensure sufficient statistical power for the primary outcome, comparing TLC with TLC with MTM among early treatment nonresponders. Sample size formula for the number of early treatment nonresponders needed for the primary analysis was equivalent to standard calculations for 2-group randomized trials. We reestimated the sample size in April 2019 using blinded data to estimate the proportion of early treatment nonresponders and proportion achieving prolonged abstinence across both groups. Seven hundred participants provided approximately 90% power to detect a 10% difference in 6-month prolonged abstinence between TLC and TLC with MTM, assuming 80% of the sample would be early treatment nonresponders and 10% would achieve prolonged abstinence with TLC.

Statistical Analysis
All analyses were intention-to-treat (ITT). All hypothesis tests were 2-sided with P < .05 considered statistically significant. Baseline characteristics were summarized overall and by the 2 comparison groups for the primary aim (defined by randomization 2A) and by the 2 comparisons groups for the secondary aim (defined by randomization 2B). To assess the primary aim (comparison of TLC with MTM vs TLC) we fit logistic regression models among early treatment nonresponders with covariates for age, baseline cigarettes per day, site, timing of assessment to early treatment (4-week vs 8-week assessment), in addition to an indicator for TLC with MTM vs TLC. A similar set of logistic regression models among early treatment responders were fit to assess secondary aim 1 (comparison of TLC to Quarterly TLC). The amount of treatment delivered was summarized by the frequencies or the median. Comparisons between randomized groups were conducted by χ 2 or Wilcoxon rank-sum test.
We addressed missing data using multiple imputation for the primary outcome and reported complete cases and additional sensitivity analyses for secondary outcomes (eTable in Supplement 2).

Results
The ITT sample used for data analysis included 636 participants. The CONSORT 29 diagram is shown in Figure 2.

Baseline Characteristics
Baseline characteristics are presented in

Discussion
The purpose of this SMART was to generate data to select components for an evidence-based adaptive intervention for smoking cessation treatment in the LCS setting. Among participants who did not respond to the initial TLC treatment, there were no significant differences in long-term or short-term abstinence between TLC with or without the availability of prescription medications.
Among participants who did respond to the initial TLC treatment, results suggested that TLC was more effective with at least monthly contact than quarterly contact, but the difference was not statistically significant. Clinically meaningful long-term quit rates were observed across TLC  .   [33][34][35] Modeling studies support that integrating tobacco treatment with LCS yields cost-benefits of similar magnitude of LCS itself; for example, adding a tobacco cessation intervention with an effectiveness of 15% results in equivalent life-years gained as increasing LCS uptake from 30% to 100%. 36 The quit rates observed in PLUTO suggest that the investment of resources to adopt a chronic care model in the LCS setting would be effective and cost-effective. Future research is needed to identify effective implementation strategies to promote adoption and integration of tobacco treatment into the LCS setting. 31 PLUTO findings are also consistent with a recent systematic review that concluded that smoking cessation interventions delivering combination counseling and medications can be successfully implemented in the LCS setting and observed that more intensive interventions are likely to be more effective than less intensive interventions. 37

Limitations
This study has limitations. The primary analysis was adequately powered, but the sample size is relatively small for some secondary outcomes. The smoking abstinence data are self-reported;

Conclusions
In this SMART clinical trial, offering a referral program to MTM along with TLC for patients continuing to smoke did not offer additional benefit. This trial supports the feasibility and use of integrating longitudinal tobacco cessation care into the LCS setting. Long-term smoking abstinence rates for longitudinal care are higher than abstinence rates observed in shorter interventions and indicate the value of taking a longitudinal or chronic care approach to tobacco cessation. Findings also show that patients undergoing LCS who smoke accept TLC, as evidenced by their completion of a relatively large number of calls over a year-long period. Health systems should consider integrating longitudinal tobacco cessation care into the LCS setting.